PROJECTSUMMARY/ABSTRACT Chronicpancreatitis(CP)isadisabling,chronicfibro-inflammatorydiseasethatimpairsqualityoflifedueto chronicpainandcomplicationsofpancreaticinsufficiency.Thereiscurrentlynoeffective,disease-modifying medicaltherapyforCP.Thecyclooxygenase-2enzyme(COX-2)isoverexpressedinthepancreasofhumans withCP,andisapromisingtherapeutictarget.COX-2producesprostaglandinE2(PGE2),apotentmediator of pancreatic chronic inflammation and stellate cell activity. Pancreas juice (PJ) PGE2 concentrations are elevated in patients with CP compared to normal volunteers. Animal studies suggest that chronic COX-2 inhibitionlessensthehistologicseverityofexperimentallyinducedCP.Asingledoseofrectalindomethacin (aCOX-2inhibitor)preventsacutepost-ERCPpancreatitis(PEP),implyingthatCOX-2inhibitioncanprevent pancreatic inflammation in humans. Indomethacin (IN) is potentially suitable for use in CP, however the pharmacodynamicsofthisdruginhumanpancreasispoorlystudied.TherearenodataregardingtheINdose requiredforsteady-stateinhibitionofhumanpancreaticCOX-2activity.Pancreasjuice(PJ)canbecollected during GIendoscopy andassayedfor PGE2,providinga safeand minimally invasive methodofassessing pancreatic COX-2 activity. The objectives of this study are: 1) to assess the physiologic effect of orally administeredINonpancreaticjuicePGE2concentrations,2)tocorrelatedrug-inducedchangesinpancreatic juice PGE2 levels with changes in salivary and blood PGE2 levels, blood IN levels, and changes in patient- reportedpainoutcome(PRO)andqualityoflife(QOL),and3)toestablishabasisforsubsequentmulticenter clinicaltrialsofchronicCOX-2inhibitioninCP. Toaccomplishtheseobjectivesapilotblinded,randomizedclinicaltrialwillbeperformedenrolling32patients withCP,whowillberandomizedtoreceive28daysofastandarddoseoforalIN(50mgBID)(16subjects) vs.placebo(16subjects).PJPGE2concentrationswillbemeasuredatbaselineandafter28daysofstudy drugadministration.PainandQOLwillalsobeassessedatbaselineandday28usingtheBriefPainInventory (BPI)andPROMIS-10questionnairesaswellasdailypainandmedicationdiaries.BloodandsalivaryPGE2 levels and blood IN levels will also be measured and correlated to PJ PGE2 concentrations. Results of this trial will inform the design of subsequent studiesof longer-term,daily NSAID administration to patients with CP, and determine whetherchanges in salivaryand/or blood PGE2 levelsareadequatefor monitoring the effect of IN onpancreatic COX-2activity. Identificationof a disease-modifying medical treatment for CP will beamajorclinicaladvanceimpactingthehealthofpersonswhosufferfromthisdisablingchronicillness.